JPH07504908A - Benzodiazepine derivatives, compositions containing them and their use in therapy - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention is useful as an antagonist of cholecystokinin and gastrin receptors. The present invention relates to benzodiazepine compounds that can be used for various purposes.

Cholecystokinin (CCK) and gastrin are present in gastrointestinal tissues and the central nervous system. Structurally interrelated pebs Raven Press, N, Y, p, 16 9 and G.

N15sion, ibid., p. 127).

Cholecystokinin is a 33-amino acid neuropeptide in its first isolated form. CCK-33 (Mut and Jorpes, Biochem, J. 125.678 (1971)), its carboxyl-terminal octapeptide. CCK-8 (also a naturally occurring neuropeptide with minimal total active sequence) ), as well as a 39-amino acid form and a 12-amino acid form. Gastrin is 34 ．． Exists in 17 and 14 amino acid forms, with the minimal active sequences CCK and Gas The C-terminal tetrapeptide Trp-M, a common structural element shared by both trines. et-Asp-Phe-NH.

Since CCK is a physiological satiety hormone, tunkard and E, 5teller, Raven Press, New York, 1984. p, 67), stimulates colonic motility, gallbladder contraction, pancreatic enzyme secretion, and promotes stomach emptying. It is believed to prevent CCK releases dopamine in certain midbrain neurons. has been reported to coexist with In addition, it may also play a role in the functioning of the dopaminergic system in the brain (A, J. Prange et al., “Peptides in the Central Nervous7 [1982]: and J, E, Morley, Life On the other hand, the main role of gastrin seems to be to stimulate the secretion of water and electrolytes from the stomach. and therefore participates in the regulation of gastric acid and pepsin secretion. Other physiological effects of gastrin Effects include increased mucosal blood flow and increased sinus motility. rat test As a result, DNA5RNA and protein synthesis increased, and gastrin It has been demonstrated that it has a positive nutritional effect on mucous membranes.

Cholecystokinin receptors include two receptors called CCK-A and CCK-B. There are at least two subtypes (T. H. Moran et al., “Two bra in cholecystokinin receptors:implica tions for behavior”, Brain Res, 362.175-79 [1986]). Both subtypes Found in both the peripheral and central nervous systems.

gastrointestinal (GI) and central nervous system (CNS) of animals, especially mammals, and more specifically humans; CCK to prevent and treat CCK-related and/or gastrin-related disorders of the and gastrin receptor antagonists are disclosed. CCK and Gust Just as there is some overlap in the biological activities of phosphorus, the antagonist also has CCK. -Tends to have affinity for both B receptors and gastrin receptors. other Antagonists of have activity against the CCK-A subtype.

Selective CCK antagonists can be used to treat CCK-related diseases of the appetite regulatory system in animals, as well as and itself useful in enhancing and prolonging opiate-mediated analgesia (P See L. Faris et al., 5science 226.1215 [1984] ), and therefore useful in the treatment of pain. CCK-B and CCK-A antagonists Furthermore, it has been shown to have a direct analgesic effect (M, F, O' Ne 1ll et al.

Brain Research, 534.287 [1990]). selective cc K and gastrin antagonists inhibit dopaminergic and serotonergic useful in the regulation of behavior mediated by the neuronal system and thus in schizophrenia and (Rasmussen et al., 199-59), palliation of gastrointestinal neoplasms. It can also be used as a drug to treat gastrin-related disorders of the gastrointestinal system in humans and animals (e.g. peptic ulcer disease). tumors, Zollinger-Ellison syndrome, sinus G cell proliferation, and reduced gastrin activity. for the treatment and prevention of other conditions that may have therapeutic value (e.g., US Pat. ．． 820.834) is useful. Certain CCK antagonists may be useful It is an anxiolytic agent and can be used to treat panic and anxiety disorders.

CCK is a stress hormone (e.g. adrenocorticotropic hormone, β-endorphin). , vasopressin and oxytocin). CCK may function as a mediator of the response to stress and part of the arousal system.

It is now known that CCK-A receptors are present in numerous regions of the CNS. , may be involved in the regulation of any of these hormones.

CCK is known for its role in the regulation of stress and its relationship with drug abuse, such as benzodiazepines. Alleviation of withdrawal syndrome (Singh et al.

1992, Br, J. Pharmacol, 105.8-10) and neuroadaptation protocols. may be involved in the process.

CCK and gastrin also exert a trophic effect on certain tumors (K, Ok ayama, Hokkaid.

Antagonists of CCK and gastrin are useful in treating these tumors. According to CCK antagonists may also be effective in neuroprotection.

CCK receptor antagonists affect the iris sphincter and ciliary body of monkey and human eyes. It has been found that it suppresses the contractile effect of CCK on muscle (Eur, J, Ph. armac9-485 [1990]), therefore inducing miosis for therapeutic purposes. It is useful for

selectively with brain CCK (CCK-B and CCK-A) and gastrin receptors Certain benzodiazepine antagonistic compounds have been reported to bind (M, Boc K et al., J. Med, Chem, 32.13-16 [1989]).

European Patent Application No. 0.167.919 specifically discloses that the and optionally substituted phenyl or C1-4 alkyl group at position 5 Discloses benzodiazepine CCK and gastrin antagonists. deer However, there is no suggestion of phenylurea substitution in the compounds of the invention.

The present invention provides formula (I): [In the formula, R1 is H; (CHt)-imidazolyl, (CHt)-tetrazolyl, (CHt), ) riazolyl (wherein q is 1.2 or 3); halo, hydroxy and NR' R' (wherein R6 and 2 units each independently represent H or Cl-4 alkyl or R6 and R7 together (CH-chain (wherein p is 4 or 5) CI-, optionally substituted with one or more groups selected from Al Kyl, C, -, cycloalkyl; cyclopropylmethyl; CH! CO*R ' (wherein Rs is Cl-4 alkyl), CH, CONR@R7 or CH lCH(OH) -W-(CHa)sNR@R' (where W is S or NH) , R6 and R7 are as defined above); R1 is a group: X represents 0, S or NRI (in the formula, R8 represents H or C1-4 alkyl) : One of Z and Y is C=O and the other is OlS or NR (wherein R1 is H or C Represents l which is (represents l-4 alkyl): R3 is C1-6 alkyl, in the formula NR@R7C, R6 and R7 are as defined above ) or represents a halo, R4 represents Cl-1e cycloalkyl; n is 011.2 or 3] The present invention provides benzodiazepine compounds and their salts and prodrugs.

When each term appears more than once in any structure herein, it has the same definition. shall be independent of the definition elsewhere in the structure.

Formula (1) includes all possible isomers including optical isomers and racemates. It is to be understood that it includes mixtures thereof.

The present invention includes within its scope prodrugs of the compounds of Formula I above. Generally speaking Prodrugs such as are readily convertible in vivo into the desired compound of formula (1). is a functional derivative of the compound of formula (1) which can be converted into of suitable prodrug derivatives. Conventional selection and manufacturing methods include, for example, “Design of Prodrugs”; Edited by H. Bungaard.

Elsevier, 1985.

Alkyl as used herein means straight chain or branched alkyl. appropriate Examples of alkyl groups include methyl, ethyl, isopropyl and isobutyl groups. Can be mentioned.

When R1 represents Cl, cycloalkyl, examples of suitable cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl groups, preferably cyclopropyl, cyclopentyl and cyclohexyl groups; It's lopropyl.

Halo includes fluoro, chloro, bromo and iodo. Preferably the halo is fluoro Or chloro.

A subgroup of compounds of the present invention includes R3 representing Cl-, alkyl or halo and R4 representing Cl- -7 cycloalkyl and n is 0, 1 or 2, by a compound of formula (1) expressed.

Preferably R1 is Cl-. Alkyl, more preferably C1-4 alkyl, e.g. Suitable examples of substituents R1 include methyl, n-propyl or isobutyl. Preferably R2 represents oxadiazolinone.

Preferably R1 is located at position 3 or 4 of the phenyl ring, more preferably at position 3 .

Suitable examples for R3 are methyl, dimethylamino, chloro and bromo.

Preferably n is O or 1, more preferably 0.

Suitable examples of R4 are cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl. It's petil. Preferably R4 represents cyclohexyl.

A preferred subgroup of compounds of the invention is of formula (IA): (1A) (In the formula, R4 has the same meaning as the above formula (1), and R'' is Cl-S alkyl, preferably represents Cl-4 alkyl) and its salts and prodrugs. .

Preferably, the salts of the compounds of formula (I) are pharmaceutically acceptable; Pharmaceutically acceptable salts may be prepared using non-sterile salts. Compound of formula (1) Pharmaceutically acceptable salts include, for example, those formed from non-toxic inorganic or organic salts. List the conventional non-toxic salts or quaternary ammonium salts of the compound of formula (1) Can be done. For example, examples of such conventional non-toxic salts include basic salts (e.g. sodium and potassium salts), inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, sulphuric acid, salts derived from organic acids (such as acetic acid, nitric acid, etc.) and organic acids (such as acetic acid, Ropionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid , citric acid, ascorbic acid, balmoic acid, maleic acid, hydroxymaleic acid , phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2- Acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethyl acetate salts prepared from (disulfonic acid, oxalic acid and isothionic acid) Ru.

The pharmaceutically acceptable salts of the present invention can be prepared by conventional chemical methods containing basic or acidic moieties. It can be synthesized from a compound of formula (I). Generally, the salt is removed in a suitable solvent or solvent. The free base or acid in various combinations of agents in stoichiometric or excess amounts of the desired salt. FormationProduced by reaction with an inorganic or organic acid or base.

For example, an acid of formula (I) may be combined with a suitable amount of a base, such as an alkali or alkaline earth metal (e.g. (e.g. sodium, potassium, lithium, calcium or magnesium) hydroxides or organic bases (e.g. amines such as dibenzylethylenediamine, trimethyl amine, piperidine, pyrrolidine, benzylamine, etc.) or quaternary ammonium React with a hydroxide (eg tetramethylammonium hydroxide).

Compounds of formula (I) antagonize CCK and/or gastrin; It is useful in the treatment and prevention of disorders, including central nervous system disorders, in which strins may be implicated.

Examples of such disease states include gastrointestinal diseases (such as peptic ulcers and duodenal ulcers). gastrointestinal ulcer, irritable bowel syndrome, gastroesophageal reflux disease, excess pancreatic secretion, excess gastrin secretion, acute pancreatitis or motility disorders), CCK and dopamine, serotonin and Central nervous system disorders caused by interactions with other monoamine neurotransmitters (e.g. For example, neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis or ・Central nervous system disorders including de Tourette syndrome; 1 disease caused by an organic disease that develops after stress related to stress, or an idiopathic disease); Schizophrenia - disorders of the appetite control system; Zollinger-Ellison syndrome, sinus and cellular hyperplasia; Including formation or pain.

The compound of formula (1) can be used to treat nervous system disorders (anxiety) involving CCK and/or gastrin. and panic disorder). This type of disability Examples of harm include panic disorder, anxiety disorder, panic syndrome, anticipatory anxiety, and fearlessness. anxiety, panic anxiety, chronic anxiety, and endogenous anxiety.

Compounds of formula (1) provide opiate or non-opiate mediated analgesia and anesthesia, i.e. It is also useful for directly inducing the disappearance of pain sensation.

Compounds of formula (1) may also be produced by chronic treatment or drug or alcohol abuse. It is also useful in the prevention or treatment of withdrawal symptoms. Non-limiting of such drugs Examples include benzodiazepines, cocaine, alcohol and nicotine .

Compounds of formula (I) are further useful in the treatment of stress and its association with drug abuse. be.

Compounds of formula (1) are further useful in the treatment of tumor disorders in which CCK may be involved.

Examples of such tumor disorders include small cell adenocarcinoma, central nervous system dahlia cell and Primary tumors of neuronal cells may be mentioned. Non-limiting of such adenocarcinomas and tumors Typical examples include tumors of the lower esophagus, stomach, small intestine, colon and lungs, including small cell lung cancer. can be mentioned.

The compound of formula (1) can be used to treat, for example, stroke, hypoglycemia, cerebral palsy, transient ischemic attack, cardiac Cerebral ischemia during cardiopulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's dance disease, Arzuno Immer disease, amyotrophic lateral sclerosis, Parkinson's disease, small olive pontine Cerebral atrophy, such as oxygen deprivation from drowning, marrow and head injuries, and environmental factors Neurodegenerative disorders resulting from pathological conditions such as intoxication by neurotoxins, including intravenous toxins It is also useful as a neuroprotective agent in the treatment and/or prevention of cancer.

The compound of formula (1) may also induce miosis for certain examinations and for therapeutic purposes after intraocular surgery. It can also be used to An example of intraocular surgery is the implantation of an artificial lens to improve whiteness. One example is internal disorder surgery. The CCK antagonist compounds of the present invention can be used for obtain.

Therefore, the present invention provides a compound of formula (r) or a salt or product thereof for use in pharmaceutical production. Provide drugs.

The present invention further provides a compound of formula (1) or a salt or prodrug thereof for therapeutic use. provide support.

In yet another aspect, the present invention provides physiological Provided are methods for the treatment or prevention of disorders, the methods comprising such treatment or prevention. Administering a CCK and/or gastrin antagonistic amount of the compound of formula (1) to a patient in need thereof consists of doing.

Compounds of Formula (I) in Human Subjects as CCK or Gastrin Antagonists If used, the daily dose will generally depend on the age, weight and response of the individual patient and the patient's symptoms. determined by the prescribing physician depending on the severity of the condition. However, in most cases Effective daily dose is about 0.005 mg to about 100 mg/kg body weight, preferably 0.05 mg/kg body weight mg ~ 5 mg ~ about 5 kg.

For example, about 0.5 mg to about 29 mg/kg body weight divided into one or several doses. Administer. However, in some cases doses outside these limits may be used. Sometimes it is necessary. For example, animal experiments have shown that doses as low as lng are effective. It has been shown that there are also

For effective treatment of panic syndrome, panic disorder, anxiety disorder, etc., it is preferable. is about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonists. Orally (p, o,) once a day or in divided doses (b, t, ct,) give Other routes of administration are also suitable.

In order to directly induce analgesia, anesthesia or loss of pain sensation - an effective dose is preferred. The dosage ranges from about 1100 n/kg to about 1 mg/kg by intravenous injection. Oral administration or Other routes of administration may also be used.

In the treatment of irritant-responsive bowel syndrome, preferably about 0.1 to 10 mg/kg. Oral administration of CCK antagonist once a day or in divided doses (b, t, ci, ) (p,o,) administered. Other routes of administration are also suitable.

central nervous system as a tumor palliative agent for gastrointestinal neoplasms harboring gastrin receptors. as a regulator of activity, for the treatment of Zollinger-Ellison syndrome or as a digestive When using gastrin antagonists for the treatment of ulcer disease, preferred Or, administer an effective dose of about 0.1 to about 10 mg/kg in 1 to 4 divided doses per day. .

For use as a neuroprotective agent, the effective dose preferably ranges from about 0.5 mg/kg to The range is approximately 20 mg/kg.

These compounds antagonize the function of CCK in animals and therefore reduce the animal's food intake. Preferably a daily dose of about 0.05 mg to 5 mg to about 5 kg body weight for increasing It may also be used as a food additive.

The compound of formula (summer) is similar to that described in European Patent Specification No. 10284256. It can be manufactured by a similar method. For example, a compound of formula (1) is a compound of formula (II) The intermediate of is expressed as (■): (11) (Il+) (In the formula, R1, R1, R3, R4 and n have the same meanings as in formula (1), and R3 and R One of 31 represents NH, and the other of R30 and R11 represents -N=C=O). It can be produced by reacting with a compound.

The reaction is preferably carried out at room temperature in a suitable organic solvent such as ether (e.g. tetrahydrochloride). Franc).

R1 is NH! The intermediate (IIA) of formula (II) representing a base (e.g. alkali gold hydrides or alkaline earth metal carbonates, such as sodium hydride or sesium carbonate. Suitable reagents for introducing the R1 group in the presence of the formula R'HaJ (formula (wherein, Hal represents halo such as bromo or iodo). or dimethylformamide in a suitable organic solvent (e.g. toluene). By reacting with a dialkyl acetal of the formula (■): (wherein, fj:, 3. R4 and n are produced from a compound of the formula (synonymous with ri, Z is a protecting group) can be done.

The compound of formula (VI) is (1) Bases (e.g. tertiary amines, e.g. triethylamine or N-methyl mol) holin) and any coupling reagent customary in peptide synthesis (e.g. 1,3-di Cyclohexylcarpodiimide (DCC), isobutyl chloroformate or preferred Preferably, bis(2-oxo-3-oxazolidinyl)phosphine chloride (BO P-CI)) in the presence of formula %formula%) (wherein Z has the same meaning as above); (n) suitably in the presence of a mercury-containing catalyst (e.g. mercury chloride (■)); ammonia gas in a clean organic solvent (e.g. ether, e.g. tetrahydrofuran). a step of processing the (ffl) an organic acid, optionally in the presence of an ammonium salt (e.g. ammonium acetate) (e.g. acetic acid or propionic acid). Formula (■): (wherein, R1, R4 and n have the same meanings as in formula (1), and R is H. ) can be produced from the compound.

The compound of formula (■) in which R11 is H can be treated with a mineral acid (e.g. hydrochloric acid) or treated with water, e.g. By base hydrolysis using aqueous sodium oxide solution, R” is C0CH, It can be produced from the corresponding compound of formula (■). The reaction takes place in refluxing methanol. It is appropriate to implement it in

Alternatively, the compound of formula (■) where R is H is the compound of formula (IX) (1x) (wherein R3 and n have the same meanings as above), a compound of the formula R4MgHal (wherein, R4 is as defined above, Hal is halo such as chloro, bromo or iodo; It can also be produced by reacting with the Grignard reagent of

The compound of formula (IX) may be a commercially available product, or may be produced from a commercially available compound by a conventional method. Good too.

The compound of formula (■) in which R11 is C0CH, is the compound of formula (X) (X) (wherein, R3 and n are synonymous with formula (1)), a compound of formula R'MgHa+ (formula Grignard test (in which Hal is halo such as chloro, bromo or iodo) It can be produced by reacting with a drug.

The compound of formula (X) can be produced by known methods, for example, A. Wal See, Sh, 5ynthesis, 677° (1980).

When a mixture of stereoisomers is produced by the above method for producing the compound of the present invention, , these isomers can be separated if desired by suitable conventional methods (e.g. preparative chromatography). ).

New compounds may be prepared in racemic form or subjected to enantiospecific synthesis or resolution. More individual enantiomers may also be produced. New compounds can be prepared, for example, by conventional methods. For example, any optically active acid (e.g. (-)-di-p-toluoyl-shi-tartaric acid and/or (+)-di-p-toluoyl After ring formation using D-Tartaric acid), fractional crystallization and regeneration of the free base resulted in dia Form a stereo pair. After formation of diastereomeric ester or amide, New compounds can also be resolved by chromatographic separation and removal of chiral auxiliary agents. can. Alternatively, new compounds can be enantiomerized by HPLC using a chiral column. Omer may be separated.

In any of the above synthetic sequences, the susceptibility or reactivity on all molecules involved It may be necessary and/or desirable to protect groups. This is for example Pro tective Groups in Organic Chemist ry, J, F, W, McOmi e@, P1 enumPress, 1973 ; and T. W. Greene and P. G. M. Wutts, Protecti. ve Gr.

Conventional protection as described in Ohn Wiley & 5ons, 1991 This can be achieved through groups. Protecting groups can be added at appropriate subsequent steps using methods known to those skilled in the art. It can be removed using

Hereinafter, the present invention will be explained in more detail with reference to Examples. Specific materials used, types and The terms are intended to further explain the invention and do not limit the scope of the invention. isn't it.

Example I N-[3(R)-5-cyclohexyl-2,3-dihydro-1-methyl-2-o Xo-IH-1,4-benzodiazepine-3-ylcoN'-[3-(5-o xo-4H-1,2,4-oxadiazolin-3-yl)phenyl] urine (+) -3(R)-amino-5-cyclohexyl-1゜3-dihydro-1-methyl-2 8-1,4-penzodiaze Step 1: (2-acetamidophenyl)cyclohexy Lumethanone Cyclohexylmagnesium bromide (2M in ether) in ether (200ml) 2-methyl-4 H-3,1-benzoxazin-4-one (100g, 0.62mof) (1) The mixture was added dropwise to an ether (1100 ml) solution. The mixture was kept at this temperature for 2 hours, then Stirred for 30 minutes at ambient temperature. -1. After cooling to 0℃, do not maintain the temperature below 0℃. The suspension was treated with 2M HCI (600ml). After stirring for 15 minutes, the layers Separate and mix the ether layer with water (500ml), 5% sodium hydroxide solution (2X5 00 ml) and finally with water (2 x 500 ml). Separate the organic layer and desorb Water (MgS04) was evaporated under reduced pressure and petroleum:ethyl acetate (2:1) was used. and chromatography on silica to obtain (2-acetamidophenyl)cyclo Hexylmethanone (28g.

24%) was obtained as a pale yellow solid. mp66℃. 'HNMR (CDCIs, 36 0MH2) 1.25 1.89 (IOH, m), 2. '23 (3H, s) , 3.33 (IH, m), 7.13 (IH, dt, J=6 and IHz), 7. 53 (IH, dt, J=6 and IHz).

7, 92 (IH, d, J=6Hz), 8. 76 (18°d, J=6H z), 11. 73 (IH, brs).

Step 2; (2-aminophenyl)cyclohexylmeth (2-acetamidophenyl methanol ( 5ml) and concentrated hydrochloric acid (15ml) were heated to 80°C over 1 hour. At this time After a while, the solution was cooled to ambient temperature and the solvent was removed under reduced pressure. Dissolve the residue in water (10 ml) ) and basified with 4N sodium hydroxide solution (20ml). then mix The material was extracted with ethyl acetate (4X 20ml), the organic layers were combined and dried (M gSO4). Evaporate the solvent and sieve using petroleum:ethyl acetate (2:1). Chromatography of the residue on lica gel gave the amine (0.40 g, 91%) was obtained as a white solid. mp73-75°C. IHNMR (360MHz, CDC Ig) 1.23 2.09 (10H, m), 3.27 (IH, m), 6.29 (2H.

brs), 6.64 (2H, m), 7.25 (IH.

dt, J=6 and IHz), 7.76 (IH, dd, J=7 and IHz).

Produce (2-aminophenyl)cyclohexylmethanone using a different procedure You can also do that. 2-Aminobenzonite in anhydrous diethyl ether (210ml) Lil (59°5g, 0.5mol) was added to the cooled (0°C) and stirred solution at a temperature of 25°C. Add cyclohexylmagnesium chloride (diethyl ether) at a rate such that the temperature remains below °C. 700 ml of 2M in solution was added dropwise. After stirring for a further 18 hours at room temperature, the mixture was It was cooled to 60°C and treated dropwise with 5N hydrochloric acid (600ml) (be careful of highly exothermic reaction). ). Next, the mixture was heated to room temperature, diluted with 5N hydrochloric acid (500 ml), and evaporated. The ether layer was separated. Basicize acidic aqueous solution to pH 4-5 with solid potassium hydroxide After that, it was extracted with ethyl acetate (3X700ml).

The ether and ethyl acetate solutions were washed together with brine (1000 ml) and dehydrated. (MgSO4) was concentrated under reduced pressure to obtain the title compound (97g, 94%). Obtained as a pale yellow solid.

Step 3: 3(R,S)-[(benzyloxycarbonyl)aminoco-5-cyc lohexyl-1,3-dihydro-28-1,4-benzodiazepin-2-one α -(isopropylthio”)-N-(benzyloxycarbonyl)glycine (30 g, 0. llmol).

It was dissolved in methane (1000ml) and cooled to 0°C. Next, the stirred solution was Tilmorpholine (11.5ml 1.0.11mol I), then formic acid i Sobutyl (13.7ml.

0, 1mol). The resulting reaction mixture was stirred for an additional 15 min at 0°C. After that, the mixture was heated to reflux temperature. (2-aminophenyl)cyclo to the refluxing reaction mixture xylmethanone (20.5 g, 0.1 mol) in dichloromethane (140 ml) ) The solution was added dropwise over a period of 20 minutes. After the addition was complete, the reaction was heated for an additional 4 hours. Heat to reflux temperature. Then mix the mixture with 10% citric acid solution (2X500ml), Saturated sodium bicarbonate solution (2 x 500 ml) and brine (500 ml each) washed. The organic phase was dried (MgSO4) and evaporated, leaving the crude product with a pale orange color. It was obtained as a solid and used without further purification.

Crude (isopropylthio)glycinamide was dissolved in anhydrous tetrahydrofuran (800 ml). ) and cooled to 0°C. After bubbling ammonia gas into the stirred solution for 30 minutes , mercuric chloride (33 g, 0.12 mo1) was added in one portion. Contains ammonia The solution was subsequently foamed for an additional 5 hours, after which the suspended solids were filtered off. Evaporate the solvent under reduced pressure This gave an oil which was used without further purification.

Crude α-aminoglycinamide was dissolved in glacial acetic acid (500 ml) and diluted with ammonium acetate. (36.2 g, 0.47 mol). The resulting reaction mixture was cooled at room temperature. After stirring overnight, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (300 ml) and I Partitioned with N sodium hydroxide solution (300ml).

The organic phase was separated, dried (MgSO4) and evaporated. 2:1 petroleum:ethyl acetate The residue was chromatographed on silica using 3(R, S)-[(benzyloxycarbonyl)aminoco-5-cyclohexyl-1,3 -dihydro-28-1,4-benzodiazepin-2-one (25 g, 64%) Obtained as a white solid. mp164-166℃. 'HNMR (360MHz, CD C13) 61.07-2.04 (IOH, m), 2.77 (IH, m), 5.12 (3H, m), 6.44 (IH, d, J=8Hz), 7.08 (IH, d, J=8Hz), 7.23-7.36 (6H, m), 7.4 6 (IH, t, J=7Hz), 7.59 (IH, d, J=8Hz), 8. 60 (IH, brs).

3(R,S)-[(benzyloxycarbonyl)aminoco-5-cyclohexyl -1,3-dihydro-2H-1,4-benzodiazepin-2-one (1,1 g, 2.8mm.

Hydrogenate the dimethylformamide (13 ml) solution at -10°C under nitrogen atmosphere. Sodium (117 mg of 55-60% dispersion in mineral oil, 2.8 mmol) once In addition, it was processed. After 30 min at −10°C, iodomethane (174 μm.

2.8 mmol) was added in one portion and the solution was brought to 0° C. over 1 hour. Then reduce the solvent. The crude residue was separated between water (100ml) and dichloromethane (100ml). Arranged. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2X100ml) . The combined organic layers were washed with brine, dried (MgSOI) and evaporated. 1: 1 Petroleum: Chromatography of the residue on silica using ethyl acetate as eluent The title compound (0.75 g, 66%) was obtained as a white solid. mp20 5-207℃. IHNMR (360MHz, CDCIg) δ1. 03-2. 04 (IOH, m).

2, 76 (IH, m), 3. 36 (3H, s), 5.10 (3H , m), 6. 52 (IH, d, J=8Hz).

7, 25-7. 55 (9H, m).

3(R,S)-[(benzyloxycarbonyl)aminoco-5-cyclohexyl -1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (3.0g.

A mixture of 7.4 mmol) and hydrobromic acid (45% in acetic acid, 6.2 ml) was added to nitrogen. The mixture was stirred at room temperature under an elementary atmosphere for 1 hour.

The mixture was then diluted with cold anhydrous diethyl ether (40 ml) and stirred at 0°C for 45 min. Stirred. The white precipitate was collected by filtration and washed with cold diethyl ether (4 x 30 ml). Dissolved in a mixture of water (30ml) and aqueous sodium hydroxide solution (2M, 15ml) did. The basic aqueous phase was extracted with ethyl acetate (3X70ml) and the combined organic layers were blotted. Line (30 ml), dried (Na2SO2) and concentrated. 94:6 jiku Lolomethane: Chromatograph the residue on silica gel using methanol as eluent. The title compound (1.6 g.

80%) was obtained as a pale pink solid. mp133-136°C. 'HNMR (360MHz, CDC1m) 61°02-1.40 (4H, m), 1 ．． 47-1.56 (IH, m), 1.61-1.74 (3H, m), 1 ．． 84-1.91 (IH, m), 1.96-2.06 (IH.

m), 2.17 (2H, br s), 2.70-2゜80 (IH, m), 3.39 (3H, s), 4.29 (IH, s), 7.20-7.27 ( 2H, m), 7°44-7.54 (2H, m).

Step 5: 3(R,S)-[2(R)(tert-butyloxycarbonyl )amino-3-phenylpropionylamino]-5-cyclohexyl-1,3 -dihydro-1-methyl-2H-1,4-benzodiazepin-2-one 3 (R ,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H -1,4-benzodiazepin-2-one (4g, 14.8mmo 1) in anhydrous Boc-D-phenyla was added to methylformamide (35 ml) solution under nitrogen atmosphere. Ranin (4.1g, 15.4mmol), 1-hydroxybenzotriazole ・Trihydrate (2,09g, 15.4mmo 1) and 1-ethyl-3-[3-( dimethylamino)propyl 1-carbodiimide hydrochloride (2.97g, 15.4mm ol) were added sequentially. Next, triethylamine (2.16m1.15.4mmo 1) was added and the resulting suspension was stirred for 20 minutes at ambient temperature. Remove the solvent under reduced pressure. and the residue was diluted with ethyl acetate (50ml) and 10% citric acid solution (50ml). distributed. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3X50ml). Yes Combine the organic phases and add 10% sodium hydroxide solution (50 ml), water (50 ml) and Washed with Bligh: / (50ml), dehydrated (MgSOs'), and evaporated under reduced pressure. I let it emanate. Clean the residue on silica using 1:1 petroleum:ethyl acetate as eluent. Chromatography gave the product (7,26,95%) as a pale yellow solid. . mp95-98°C. 'HNMR (360MHz.

CDCl5) 60.99-1.11 (IH, m), 1°16-1.72 ( 7H, m), 1.40 (9H, s).

1.83-1.92 (IH, m), 1.98-2.06 (IH, m), 2.73-2.83 (IH, m).

3.10-3.24 (2H, m), 3.38 (3H, s), 4. 53 (LH, brs), 4. 98 (IH, brs), 5. 28-5.　 34 (2H, m), 7. 19-7, 32 (7H, m), 7. 49 -7. 58 (2H,m)3 (R,S)-[2(R)-(tert-butyl oxycarbonyl)amino-3-phenylpropionylamino]-5-cyclo Xyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2 -on (4,7g.

9.1 mmol) was dissolved in ethyl acetate (20 ml) and cooled to 0°C. Next The solution was saturated with hydrogen chloride gas.

After 1 hour and 30 minutes, the resulting precipitate (which may be an undesired diastereoisomer) R, = 0.04 ethyl acetate) was filtered off and the filtrate was evaporated. Vinegar solid residue The organic The phases were separated and the aqueous phase was extracted with ethyl acetate (2X25ml). Combine the organic phase Dehydrated (Na!S04) L and evaporated under reduced pressure. 0→20 in ethyl acetate Chromatograph the residue on silica using a gradient elution of % methanol. , the title compound (1.66 g, 44%, R, = 0.13 ethyl acetate) was converted into a pale yellow solid. obtained as. mploO-103°C. 'HNMR (360MHz, CDC1s ) δ1゜00-1.39 (4H, m), 1.50-1.72 (4H, m) , 1.84-1.92 (IH, m), 2.00-2.07 (IH, m) , 2.72-2.84 (IH.

m), 2.79 (IH, dd, J=13.8 and 9.8Hz), 3.28 (IH, dd, J=13.8 and 4°0Hz), 3.40 (3H, s), 3.69 (IH.

dd, J=9.8 and 4.1Hz), 5.36 (IH.

d, J=8.3Hz), 7.21-7.36 (7H, m), 7.47-7 ．． 58 (2H, m), 8.66 (IH.

d, J=8.3Hz). [a]”o+32.7° (c=0°58, CHsO H).

Use the following procedure to identify the undesired diastereoisomer (RfO,04, acetic acid ester). 3(R,S)-(2(R)-amino-3-phenylpropionyl) (mino)-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1゜4- It can be epimerized to benzodiazepine-2-ones.

Undesired diastereoisomer (Rfo, 04.ethyl acetate) (16,8 g, 0.044 mol) in anhydrous ether (200 ml), potassium-ter t-Butoxide (0.68 g, 6.1 mmo 1) was added. Mixture at room temperature After stirring for an hour, additional potassium tert-butoxide (0.68 g, 6.1 m mo1) was added and the mixture was heated to reflux temperature for 5 hours. Then bring the mixture to ambient temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (200 ml) and water (200 ml). 00ml). Separate the organic layer, dry (MgSO4), filter and vacuum The epimerized material was obtained by evaporation to the bottom.

Step s: (+) -N-[1(R)-2-[3(R)-5-cycloheki Sil-2,3-dihydro-1-methyl-2-oxo-IH-1,4-benzodia zepin-3-yl)aminoco-2-oxo-1-(phenylmethyl)ethyl]- N’-phenylthiourea (+)-3(R)-(2(R)-amino-3-phenylpropionylamino )-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-ben Zodiazepin-2-one (1.6 mg, 3.83 mmo 1) in anhydrous dichloromethane Phenyl isothiocyanate (0.5ml 1.4.21mm) ol) and then heated on a steam bath for 30 minutes. Evaporate the solvent under reduced pressure Chromatograph the residue on silica using 1:1 dichloromethane, The product (2.1 g, 100%) was obtained as a pale yellow solid. mp129-13 2°C, 'HNMR (360MHz, CDCl5) 60.95-1.07 (IH , m), 1.15-1.37 (3H, m), 1.45-1.69 (4H , m), 1.81-1.88 (IH.

m), 1.93-2.00 (IH, m), 2.70-2.80 (IH, m), 3.24-3.41 (2H, m), 3.38 (3H, s), 5 ．． 23 (IH, d, J=7.3Hz), 5.31-5.40 (IH, m) , 6°67 (IH, 7°0Hz), 6.87-7.02 (2H.

m), 7.20-7.35 (9H, m), 7.46-7.52 (2H, m ), 7.65 (IH, s). [α] 2 convergence + 27.3' (c = 0.31.C HICIri.

Step 9: (+)-3(R)-amino-5-cyclohexyl-1,3-dihydrogen Dro-1-methyl-2H-1,4-benzodiazepin-2-one N-[1(R)-2[(3(R)-5 dichlorohexyl-2,3-dihydro-1 -Methyl-2-oxo-IH-1゜4-benzodiazepin-3-yl)aminoco -2-oxo-1-(phenylmethyl)ethyl]-N'-phenylthiourea (4 , 5g, 8.1mmo 1) was dissolved in trifluoroacetic acid (25ml) and heated to ambient temperature. The mixture was stirred at 30°C for 30 minutes. The trifluoroacetic acid was removed under reduced pressure and the residue was dissolved in dichloromethane. Toluene (2 x 20 ml) and toluene (2 x 20 ml) were added to azeotrope.

9o:io:o, too, 1 dichloromethane; methanol: acetic acid: water as eluent Chromatograph the residue on silica gel using A sticky substance was obtained. This was dissolved in ethyl acetate (150 ml), cooled to 0°C, % sodium carbonate solution (15 ml). Dilute with water (25 ml) and 1 minute After stirring for a while, the organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2X50ml).

The organic layers were combined, dried (NatSO4) and evaporated under reduced pressure. The title compound (1.56 g, 71%) was obtained as a solid with a yield of 99%. mp13 3-136℃. 'HNMR (360MHz, CDCIs) δ1.01-1.　 39 (4H, m), 1. 50-1. 54 (IH.

m), 1.60-1. 70 (3H, m), 1.84-1.92 (IH , m), 1.96-2.04 (IH, m), 2. 36 (2H, brs ), 2.70-2. 80 (IH, m), 3.41 (3H, s), 4. 32 (IH, s), 7. 22-7.28 (2H, m), 7.46-7 ．． 58 (2H, m). [α1! 3o+33.2° (C=0.66, C HsOH).

Intermediate 2 l-(5-oxo-4H-1,2,4-oxadiazolin-3-yl)-3-a Minobenzene hydrochloride Step 1: 1-cyano-3-tert-butyloxycarbo Nylaminobenzene 3-Aminobenzonitrile (47g, 0.40mo1) in dichloromethane (2 di-tert-dibutyl carbonate (132 g, 0.60 m A solution of o l) in dichloromethane (150 ml) was added. The mixture was kept under reflux for 4 days. After heating to 20°C, the mixture was cooled to room temperature and 10% citric acid solution (200ml) was added. and stirred. Separate the organic layer and dilute the aqueous phase with dichloromethane (3X100ml). Extracted. The combined organic layers were washed with brine (100ml) and then separated. Detachment After water (Na!5O4) the solvent was evaporated to give a beige solid. This oil Triturate with ether (60/80) to give the desired product as a white solid (65,9 g .

7.5%). mp123-126℃. IHNMR (360MHz , CDC1g) 61.52 (9H.

s), 6.50 (IH, brs), 7.29 (IH.

d, J=8Hz), 7.36 (IH, dd, J=8 and 8Hz), 7.51 (IH, d, J=8Hz), 7°76 (IH, s).

(Prepared by dissolving 1.17 g of sodium in 70 ml of ethanol) Hydroxylamine hydrochloride (3, 16 g, 0.045 mol) was added. The mixture was stirred at room temperature for 15 minutes, then 1 -cyano-3-tert-butyloxycarbonylaminobenzene (3,00g , 0.014 mo 1) was added. The mixture was heated to 50 °C overnight and then brought to ambient temperature. It was cooled to The mixture was then filtered and the filtrate was evaporated under reduced pressure.

The residue was partitioned between ethyl acetate (50ml) and water (50ml). Separate the organic phase; The aqueous phase was extracted with ethyl acetate (3X20ml). Combine the organic layers and brine (5 0 ml), and then dehydrated (Na*5Os). Evaporate the solvent and turn pink A colored foam was obtained. After the foam was left at 0°C overnight, it was diluted with 1:1 petroleum:ethyl acetate. In addition, it was crushed. The title compound was collected as a white solid (2.52g, 73%). . IHNMR (360MHz, DsDMSO) δ1.47 ( 9H.

s), 5.69 (2H, brs), 7.24 (2H.

m), 7.41 (IH, brd, J=6.5Hz).

7.82 (IH, s), 9.35 (IH, s), 9°58 (IH, s), MS (C1, NHs) 252 (M+1).

Amidoxime (0.68g, 2.7.mmo 1) in tetrahydrofuran (1 0 ml) 1.1'-carbonyldiimidazole (0.53 g, 3° 3 mmol) was added. After stirring the solution overnight at room temperature, a white solid precipitates from the solution. did. The mixture was then heated to reflux for 5 hours and then allowed to cool to ambient temperature. solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (50 ml) and 10% citric acid solution ( 50 ml). The organic layer precipitated as a white solid and was collected by filtration.

The solid was confirmed to be the desired oxadiazolinone (0.53 g, 71%). Ta. mp186-189℃. IHNMR (360MHz, Do DMSO) δ1 ．． 49 (9H, s), 7.36 (IH, d, J=9Hz), 7°44 ( IH, dd, J=8 and 8Hz), 7.58 (IH, d, J=9Hz), 8 ．． 07 (IH, s), 9゜64 (IH, s), 13.00 (IH, b rs).

Step 4: 1-(5-oxo-48-1,2,4-oxadiazolin-3-yl )-3-aminobenzene hydrochloride 1-(5-oxo-4H-1,2,4-oxadi azolin-3-yl)-3-tert-butyloxycarbonylaminobenzene (0.8g, 2.9mmo 1) was dissolved in ethyl acetate (40ml) and cooled to 0℃. Rejected. Hydrogen chloride gas was then bubbled into the stirred solution for 10 minutes. 10 nitrogen into the mixture After bubbling for a minute, the solvent was evaporated under reduced pressure. Toluene (2x20ml) to the residue was added to azeotrope the mixture, and then ether was added and the mixture was pulverized. Title compound (0.59g, 95%) was isolated as a white solid. mp238-242°C (decomposition).

' HN M R (360 MHz, D @ D M S O) δ7.33 (IH, m), 7.51-7.54 (3H, m).

1-(5-oxo-4H-1゜2.4-oxadiazolin-3-yl)-3-a Anhydrous tetra of minobenzene hydrochloride [intermediate 2] (281 mg, 1.3 mmol) Human 07 run (25 ml) suspension was diluted with triethylamine (0,36 m1.2.6mmo 1) Treated by dropping.

The mixture was then cooled to 0°C and triphosgene (1 @ 27 mg) was added.

After adding triethylamine (0°36ml, 2.6mmol) o1) was added dropwise. After stirring the mixture for 5 min at 0 °C, the cooling bath was removed and the ambient Stir at temperature for 10 minutes. The mixture was then cooled to 0°C and (+)-3R-amino- 5-Cyclohexyl-1,3-dihydro-1-methyl-28-1,4-benzodi Azepin-3-one [intermediate 1] (245 mg, 0.9 mmo 1) in anhydrous solution A solution of trahydrofuran (4 ml) was added dropwise. After addition, stir the suspension at 0°C for 5 min. After stirring, the cooling bath was removed and the mixture was stirred at room temperature for 30 minutes. Then filter the mixture and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (20 ml) and 20% acetic acid. Partitioned with aqueous solution (20ml). Separate the organic layer and add 20% aqueous acetic acid solution (20 ml ) and then washed once again with brine (20 ml). The organic phase was separated and dried (N alSO4) and evaporated. Dissolve dichloromethane:methanol (97:3) Chromatograph the residue on silica gel as a release agent to viscous the desired product. Obtained as a liquid oil. Add dichloromethane (2X20ml) to this, then toluene. (2×20 ml) was added and azeotroped. Then, the resulting white solid was added with anhydrous ether. was added to give the desired urea (310 mg, 73%) as a white solid. m p216-218°C (petroleum (60/80)/EtOAc). IHNMR (360 MHz, DsDMSO) δ0.91 (IH, m), 1°09 -1.91 (9H, m), 2.93 (IH, m).

3, 32 (3H, s), 5. 07 (IH, d, J=8Hz), 7. 32-7. 44 (4H, m), 7. 55 (2H, m), 7.64 (IH, dd, J=8 and 8Hz), 7.75 (IH, d, J=8Hz), 7.91 (IH, s), 9. 25 (IH, s).

Example 2 N-[3(R,5)-5-cyclobutyl-2,3-dihydro-1-methyl-2- Oxo-IH-1,4-benzodiazepin-3-yl]-N'-[3-(5 -oxo-4H-1,2,4-oxadiazolin-3-yl)phenyl]urea Step 1: 2-aminophenylcyclobutylmethanone cycloptyl bromide (1 3 g, 0.1 mol) in diethyl ether (150 ml) at reflux temperature. Magnesium turnings (2.5 g) in chill ether (20 ml).

It was added dropwise to a slurry of 0.11 mo I) and iodine crystals over 1 hour. blend After stirring for an additional hour, the solution was added dropwise under equal pressure in a three-necked round-bottomed flask under a nitrogen atmosphere. The Grignard solution was injected into the funnel through the cannula.

Aminobenzonitrile (3.78 g, 32 mm) at 0°C.

Grignard solution of l) in diethyl ether (50 ml) prepared as above. The reagent was added dropwise for 15 minutes.

Once the addition was complete, the mixture was warmed to room temperature and stirred for 16 hours under nitrogen atmosphere. . The solution was cooled to 0°C, quenched with 5N hydrochloric acid (20ml) and dissolved in solid sodium hydroxide. The mixture was basified using Um (4 g). Aqueous solution in ethyl acetate (2X100ml) The combined organic layers were dried (NalSO4) and evaporated. 2:1 oil :Chromatograph the residue on silica gel using ethyl acetate as eluent. I put it on. A yellow oil was thus obtained which was azeotroped by adding toluene (2X80ml). The title compound (4 g, 71%) was obtained as a pale yellow solid. mp55℃. IH NMR (250 MHz, CDC1s) δ1.72-2.48 (6H, m).

3.80-4.00 (IH, m), 6.23 (2H, brs), 6.5 0-6.61 (2H, m), 7.11-7.22 (IH, m), 7.4 5-7.54 (IH.

m).

Step 2: 3(R,S)-[(benzyloxycarbonyl)aminoco-5-cyc butyl-1,3-dihydro-28-1,4-benzodiazepin-2-one α- Isopropylthio-N-benzyloxycarbonylglycine The methane (200ml) solution was cooled to 0°C. N-methylmorpholine (3.3m After adding 1.29.7 mmo 1) over 2 minutes, isobutyl chloroformate (3 ．． 9m1.29.

7 mmol) was added. After stirring the mixture for 15 minutes at 0°C, the mixture was refluxed. heated to temperature. 2-aminophenylsic in anhydrous dichloromethane (20ml) Butyl methanone (4 g. 22.9 mmol) was added to the reaction mixture at reflux temperature for 10 minutes. The mixture was stirred at reflux temperature for 1.5 hours. The reaction mixture is N citric acid (100 ml), water (100 ml), saturated sodium bicarbonate solution (1 00 ml) and brine (100 ml). Dehydrate the organic phase (N a ! SO 4) Evaporate and add toluene (2X100ml) to azeotrope A yellow oil was obtained. Add 7:1 petroleum:ethyl acetate and grind to obtain the product (8 g. 80%) was obtained as a colorless solid. This material was used without further purification.

Anhydrous tetrahydrofuran solution (300 ml) was cooled to 0°C and heated with ammonia gas. It was saturated. This solution No.2 glycinamide prepared as above (8 g, 18 m mo 1), then mercuric chloride (7.4 g, 27 mmol) was added. a The mixture was stirred at 0° C. for 1.5 hours with continuous bubbling of ammonia gas. mixture Filter the material through hyflo and evaporate the filtrate to give the desired amine as a colorless waxy solid. I got it. This material was used without further purification.

The amine prepared above (6.9 g, 18 mmol 1) was mixed with acetic acid (250 ml). ) and treated with ammonium acetate (6°5 g, 84.6 mmol 1).

The mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. Evaporate the solvent and remove the residue. Partition between ethyl acetate (250ml) and 10% sodium hydroxide solution (100ml) did. The organic phase was separated, dried (Na!S04) and evaporated to a yellow solid. I got it. Add diethyl ether and triturate to obtain the title compound (3.8 g, 50%). Obtained as a colorless solid. mp200-202℃. TLC (silica, petroleum: ethyl acetate) 2:1). Rf 0.3° wide HNMR (250MHz, CDCI 3) δ 1. 60-2゜80 (6H, m), 3.70 (IH, m), 5.12 (2H, m), 5.22 (IH, d, J=8Hz).

6.50 (IH, d, J=8Hz), 7.02-7.53 (9H, m), 9.44 (IH, s).

Step 3: 3(R,S)-[(benzyloxycarbonyl)aminoco-5-cyc Butyl-1,3-dihydro-1-methyl-28-1,4-benzodiazepine- 3-one 3(R,S)-[(benzyloxycarboxylic acid) in anhydrous toluene (70 ml) (bonyl)aminoco-5-cyclobutyl-1゜3-dihydro-2H-1,4-ben Zodiazepin-3-one (Ig, 2.75 mmol) was heated to reflux temperature. Ji Methylformamide dimethyl acetal (1,75ml1゜13.7mmol) Anhydrous toluene (10 ml) solution was added dropwise and the mixture was heated to reflux for a further 3 hours. Ta. The solvent was evaporated and the residue was triturated with diethyl ether to give the title compound (0 , 75 g, 72%) as a colorless solid. mp210-211℃. 'HNMR (250MHz, CDCl5) δ1.68-2.06 (4H, m), 2.2 0-2.60 (2H, m), 3.41 (3H, s), 3゜60-3.80 (IH, m), 5.00-5.30 (3H, m), 6.51 (IH, d , J=14Hz), 7.14-7.54 (9H, m).

1,3-dihydro-1-methyl-2H-1,4-benzine 3 (R,S)-[( benzyloxycarbonyl)aminoco-5-cyclobutyl-1,3-dihydro- 1-Methyl-28-1,4-benzodiazepin-2-one (400 mg.

1.06 mmol) was treated with 45% hydrogen bromide in acetic acid (10 ml) for 20 min. The mixture was stirred at room temperature for a while. The mixture was then added dropwise to cold (0°C) diethyl ether (50ml). I put it down. The precipitated white solid was filtered off. The solid was dissolved in 10% sodium hydroxide solution (5% 0 ml) and then extracted with ethyl acetate (80 ml). Separate and desorb the organic layer. Water (Na, S04) and evaporated gave a yellow foam. This substance It was then used without further purification.

Step 5: N-[(3(R,5)-5-cyclobutyl-2,3-dihydro-1- Methyl-2-oxo-IH-1゜4-benzodiazepin-3-yl]-N' -[3-(5-oxo-48-1,2,4-oxadiazolin-3-yl)phene [Nil] Urea 1-(5-oxo-4H-1,2,4-oxadiazolin-3-yl)-3-a Minobenzene hydrochloride (330 mg.

A suspension of 1.54 mmol) in anhydrous tetrahydrofuran (25 ml) was diluted with triethyl Amine (428μ1.3.08mm.

l) and stirred for 5 minutes at room temperature. After cooling the mixture to 0 °C, tryphosge (151 mg, 0.51 mmol) was added. The mixture was stirred for 2 min at 0°C. After that, triethylamine (428μm, 3.08mmo 1) was added dropwise and the solution was The pH was adjusted to 9. The mixture was then stirred for a further 5 minutes and warmed to 15°C before 0. Recooled to °C. Next, 3(R,S)-amino-5-cyclobutyl-1,3-di Hydro-1-methyl-2H-1,4-benzodiazepin-2-one (251 mg , 1.06 mmo 1) in anhydrous tetrahydrofuran (4 ml) for 5 minutes. dripped. The mixture was stirred at 0°C for 5 minutes, allowed to warm to room temperature, and then for an additional 40 minutes. Stir for a while. Insoluble matter was filtered off. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate ( 20 ml) and a 20% acetic acid aqueous solution (10 ml). Separate the organic phase and dehydrate (NalSO4) and evaporated. 0→5% gradient of MeOH in dichloromethane The residue was chromatographed on silica gel by partitioning elution.

Triturate with diethyl ether to obtain the product (130 mg.

25%) was obtained as a colorless solid. mp225°C (decomposition).

'HNMR (360MH2, D@DMSO) δ1.72-1.87 (IH , m), 1.92-2.12 (3H.

m), 2゜27-2.42 (IH, m), 2.46-2, 59 (IH, m) , 3.43 (3B, s), 3゜72-3.84 (IH, m), 5.3 8 (IH, d, J-6Hz), 7.22-7.66 (8H, m), 7°7 0 (IH, d, J=8Hz), 7.81 (IH, s).

N-[3(R,5)-5-cyclohexyl-2,3-di1B Tsuji'nimfk-22 ! Earth Muyo' upper knee L Niji 1 Otsu L1 body = 2 Otsu blood Shigo (2' 1 Nie shadow Go 19≧1± -1, 2 Two soils two reno l again left ≦ Hi A mutual and L gong” Shiurea 1-(5-oxo-4H-1,2,4-oxadiazolin-3-yl)-3-a Anhydrous tetite of minobenzene hydrochloride [intermediate 2] (57 mg, 0.27 mmo 1) A suspension in 5 ml of radofuran was added to a suspension of triethylamine (75 µI) under a nitrogen atmosphere. , 0.55 mmo+) dropwise. The mixture was then cooled to 0°C and Sugen (26 mg, O.

Q9mmol) and then triethylamine (75μm, 0.55mmol ) was added dropwise. The mixture was then stirred at 0 °C for 5 min, after which the cooling bath was removed and the mixture was heated to ambient temperature. The mixture was stirred for 10 minutes at a temperature of The mixture was then cooled to 0°C and the 3(R,S)-amino- 5-Cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodi Azepin-3-one [Intermediate 1, Step 5] in anhydrous tetrahydrofuran (3 ml) The solution was added dropwise. After the addition, the suspension was stirred at 0 °C for 5 min, then the cooling bath was removed. , the mixture was stirred at room temperature for 20 minutes. Then filter the mixture and evaporate the filtrate under reduced pressure. I let it happen. The residue was partitioned between ethyl acetate (20 ml) and 20% aqueous acetic acid solution (20 ml). did. The organic layer was separated and treated with 20% aqueous acetic acid (20 ml), then brine (20 ml). ml) again. The organic phase was separated, dried (Na!1o4) and evaporated. Ta. Treat the residue with dichloromethane:methanol (97:3) and filter off the insoluble solids. did. A white solid (35 mg, 41%) was confirmed to be the desired urea. Ji Filter the filtrate on silica gel using chloromethane:methanol (97:3) as eluent. Chromatography gave the title compound (9 mg, 10%) as a white solid. . mp197-199°C. 'HNMR data were as described in Example 1. .

Compound of formula (I) 1.0 2.0 25.0 Microcrystalline cellulose 20.0 2 0.0 20.0 Modified Food Cornstarch 20.0 20.0 20.0 Lac Tos 58.5 57.5 34.5 Magnesium stearate 0.5 0 ．． 5 0.5 Formula (1) (7) Compound 26. Q 50.0 100.0 microcrystal buying Cellulose 80.0 80.0 80.0 Modified food cornstarch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 Steer Magnesium phosphate 0.5 0.5 0.5 Compound of formula (I), cellulose, Mix some lactose and corn starch to make 10% corn starch paste It also became granular. The generated granules are sieved and dehydrated to remove residual cornstarch. and magnesium stearate. The produced granules are then compressed into one tablet. per 1.0mg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and Tablets containing 100 mg of active compound were made.

Compound of formula (1) 1-100 Citric acid-hydrate 0.75 Sodium phosphate 4.5 Sodium chloride 9 Water for injection up to 1ml Sodium phosphate, citric acid-hydrate and sodium chloride were dissolved in a portion of water. . The compound of formula (1) was dissolved or suspended in this solution and diluted.

Compounds of formula (I) 1-10 Emulsifying wax 30 Liquid paraffin 20 White soft paraffin 1001te The white soft paraffin was heated until it melted. Liquid paraffin and emulsifying wax and stirred until dissolved. Add the compound of formula (1) until dispersed Continued stirring. The mixture was then cooled to a solid.

Sulfated CCK-8 was purified using “I-Bolton-Hunter reagent (2000Ci/ Radioactively labeled with mmo1e).

Chang and Lo t t i (Proc, Na t 1. Acad, Sci., 83.4923-4926.1986) with slight modifications. Thus, receptor binding was performed.

Male Sprague-Dawley rats (150-200 g) were sacrificed by decapitation. did. The whole pancreas was incised, adipose tissue was removed, and 0.1% soybean trypsin inhibitor was added. Ice-cold IQmMN-2-hydroxyethyl-piperazine-N'-2-etha containing Kin sulfonic acid (HEPES) buffer (pH 7°4.25°C) in 25 volumes. It was homogenized using ematica Polytron. Homogenate to 47.8 Centrifuged at 00g for 10 minutes. Teflon(TM) Homogenizer (500 10 volumes of binding assay buffer (20 m M (HEPES), 1mM ethylene glycol-bis-(β-aminoethyl ethyl ter-N,N'-tetraacetic acid) (EGTA), 5mM Mgcl*, 150m M NaCl, bacitracin 0.25mg/mz, soybean trypsin inhibitor 0.1 mg/ml and bovine serum albumin 2mg/mj! (pH 6, 5, 25℃)) The pellet was resuspended in the solution. The homogenate was further diluted with binding assay buffer. to give a final concentration of 0.5 mg wet weight/1 ml buffer. Binding assay tagiku buffer (for total binding), unlabeled sulfated CCK-8 (non-specific 50 μl of the compound of formula (for measuring the inhibition of 1-CCK-8 binding) and 500 pM “’I-CCK-8.50 μl (i.e. 50 pM final concentration) was added to the matrix. Added to 400 μl of membrane suspension in a microcentrifuge tube. Repeat all the steps twice. provided. The reaction mixture was incubated for 2 hours at 25°C and incubated with Whatman GF /C by rapid filtration on filter paper (Brandell 24-well cells)\-Bester) The reaction was terminated and washed with 3x4mf of ice-cold 100mM NaCl. on filter paper Radioactivity was counted with an LKB gamma counter.

2. CCK receptor binding (brain) Sulfated CCK-8 was radiolabeled using a slightly modified method described for the pancreas. Binding was performed in the following order.

Male Hartley guinea pigs (300-500 g) were killed by decapitation and the skin The material was removed and homogenized in 25 mL of water-cooled 0.32 M sucrose. homogenate Centrifuge at 1000g for 10 minutes, and centrifuge the resulting supernatant at 20,000g for 20 minutes. Centrifuged again. Tef Ion(TM) Homogenizer (500 rpm Binding assay buffer (20mM HEPES, 5mM M MgC1! , 0.25mg/+nl bacitracin, 1mM EGTA, pH Resuspend the P2 pellets in 10 mg wet weight/1.2 mj ! The final concentration of buffer was taken.

For binding assays, buffer (for total binding), unlabeled sulfate at a final concentration of 1 μM. CCK-8 (for non-specific binding) or compounds of formula I for inhibition of C25I-CCK-8 binding. 50 ul (for measurement of harmful effects) and 50 ul (i.e. 5 (M) M final concentration) was added to 400 μl of membrane suspension in a microcentrifuge tube. All a The experiment was repeated twice.

After incubating the reaction mixture for 2 hours at 25°C, whatman GF/C Reaction by rapid filtration on filter paper (Brandell 24-well cell harvester) Finish with 3x5mf of cold 100mM NaC! Washed with. Radioactivity on filter paper Counting was performed using an LKB gamma counter.

In vitro results Effect of compound of formula (■) on 5l-CCK-8 receptor binding Preferred compounds of formula ) produces a dose-dependent inhibition of specific “I-CCK-8 binding, defined as the difference between It is a compound that causes

Perform drug displacement studies using at least 10 concentrations of a compound of formula I and IC5o values were determined by analysis.

IC5o value ft　”’I　CCK-3 (required to inhibit 50% of D-specific binding) means the concentration of the required compound.

The data in Table 1 were obtained for compounds of formula I.

Table 1 CCK receptor binding results I.C. (nM) Compound “’I-CCK”l-CCK1’ 500 0.123 2 110 5.98 1,, IW-~Stirrup PCT/GB 93100535 Continuation of front page (51) Int, C1,' Identification symbol Internal office reference number A61K 31155 ADP 9454-4CADS 9454-4C (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, S E), AU, CA, JP, US (72) Inventor Chambers, Mark Stuart UK, Hertfordshire W.D. 2.2. B.R., Watford, North Putsey, Park Avenue Mezzo Nettutsu・10 I (72) Inventor: Fletcher Stephen Robert, United Kingdom, Hartford Dosha C.M. 22.7 E.G., Near Bishop's St. Torford, Hatfield Heath, Crimpt Hedge 10 (72) Inventor Matatsusa, Pictor Giulio Hertford, UK Shah Nis Gee 9.0 El Ni, Farnyx Pelham, The De Zutsk Street Barns (no street address)

Claims (10)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is H; (CH2)q imidazolyl, (CH2)q tetrazolyl, (CH2) q triazolyl (wherein q is 1, 2 or 3); halo, hydroxy and NR 9R7 {wherein R6 and R7 each independently represent H or C1-4 alkyl or R6 and R7 taken together (CH2) p chain (where p is 4 or 5 ) C1-6 atom optionally substituted with one or more groups selected from C3-7 cycloalkyl; cyclopropylmethyl; CH2CO2R5 ( where R5 is C1-4 alkyl); CH2CONR6R7 or CH2CH (OH)-W-(CH2)2NR6R7 (where W is S or NH, R6 and and R7 are as defined above); R2 is a group; ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ {During the ceremony, X represents O, S or NR8 (in the formula, R8 represents H or C1-4 alkyl); One of Z and Y is C=O and the other is O, S or NR9 (wherein R9 is H or represents C1-4 alkyl); R3 is C1-6 alkyl, NR6R7 (wherein R6 and R7 have the same meanings as above) ) or represents a halo, R4 represents C3-10 cycloalkyl; n is 0, 1, 2 or 3] benzodiazepine compounds and their salts and prodrugs. 2. R3 represents C1-6 alkyl or halo, R4 represents C3-7 cycloalkyl and n is 0, 1 or 2. 3. 3. The compound according to claim 1 or 2, wherein R1 is C1-6 alkyl. 4. The compound according to any one of claims 1 to 3, wherein R2 is oxadiazolinone. Compound. 5. N-[3(R)-5-cyclohexyl-2,3-dihydro-1-methyl-2 -oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(5- Oxo-4H-1,2,4-oxadiazolin-3-yl)phenyl]urea; N-[3(R,S)-5-cyclobutyl-2,3-dihydro-1-methyl-2- Oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(5-o xo-4H-1,2,4-oxadiazolin-3-yl)phenyl]urea; N-[3(R,S)-5-cyclohexyl-2,3-dihydro-1-methyl-2 -oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(5- Oxo-4H-1,2,4-oxadiazolin-3-yl)phenyl]urea; A compound according to claim 1 selected from: and salts and prodrugs thereof. 6. 6. A compound according to any one of claims 1 to 5 for therapeutic use. 7. Any of claims 1 to 5 together with a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition containing a compound according to item 1. 8. The intermediate of formula (II) is expressed as formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼( II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R1, R2, R3 , R4 and n have the same meanings as in formula (I) above, and one of R30 and R31 represents NH2. and the other of R30 and R31 represents -N=C=O). A method for producing the compound according to any one of claims 1 to 5, comprising: 9. For the production of pharmaceuticals for the treatment of physiological diseases related to CCK and/or gastrin. 6. Use of a compound according to any one of claims 1 to 5 for. 10. Claims 1 to 5 for the manufacture of a medicament for treating panic, anxiety or pain Use of a compound according to any one of the clauses.